Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV) are related human gammaherpesvirus and important pathogens in immunocompetent and immunosuppressed hosts. Oral transmission is the primary mechanism for EBV infection, and oral EBV infection is associated with nasopharyngeal carcinoma and oral hairy leukoplakia. The importance of oral transmission for KSHV infection remains to be determined, but persistent oral infection and oral virus shedding are common features for EBV and KSHV infections. However, in both instances oral viral infection is poorly understood including the cell types infected in the oral cavity, the viral genes important for oral transmission, primary infection and viral persistence, the role of oral epithelial cell versus lymphocyte infection, and the mucosal immune responses important for controlling oral infection. This program will combine virology, immunology, and pathology expertise to address fundamental issues in the oral biology of gammaherpesvirus infection in immunocompetent and immunosuppressed hosts. The recent discovery, cloning and sequencing of two gammaherpesviruses closely related to EBV and KSHV and naturally infecting rhesus macaques provide new experimental animal models wand will serve as a starting point to define the biology of oral gammaherpesvirus infection and to experimentally test the role of specific viral genes in vivo. Advances in defining KSHV-specific immune responses, mucosal immune responses to other viral antigens, and immune responses in the macaque animal model will be applied to better understand the immunology of oral gammaherpesvirus infections. An antibody core will develop new antibody reagents for these studies, and a pathology core will coordinate, develop, and apply innovative pathologic methods to study and detect oral viral infections. Translation of results from animal models to human studies is an important and intrinsic component of the program. This program will combine the comparative powers of studying closely related gammaherpesviruses with the synergy of clinicians, virologists, pathologist, and immunologist to better understand the oral pathogenesis of gammaherpesvirus infections in immunocompetent and immunosuppressed hosts.